Primary and secondary malignancies of the brain are routinely subject to radiotherapy in combination with concurrent and adjuvant chemotherapy, frontline treatments that remain the only tenable option for providing a restraint on disease progression. Unfortunately, debilitating cognitive side effects result from these treatments, and growing numbers of patients are surviving longer with severe neurocognitive sequelae. The negative impact of treatment-induced cognitive dysfunction is becoming increasingly recognized as a critical criterion for evaluating therapeutic outcome and for determining long-term quality of life. Thus, we propose a series of novel studies to elucidate the mechanistic basis of radiation and chemotherapy-induced cognitive impairment. Mice will be subjected to irradiation and chemotherapy paradigms designed to approximate clinical treatment scenarios, with a focus on a combined regimen of fractionated irradiation and temozolomide (TMZ) that is commonly used for the treatment of brain cancer. Rigorous behavioral assessments conducted at early (2 month) and latter times (6 months) post-treatment, will be coupled with molecular, cellular and electrophysiologic studies designed to test our overarching hypothesis that disruptions to neuronal anatomy and CB1 signaling are contributory if not causal to many of the unintended cognitive decrements caused by current cancer treatment regimes. We have quantified a range of neuronal morphometric parameters at different doses and times after irradiation and/or chemotherapy and found both marked and persistent reductions in dendritic complexity and spines that are temporally coincident with changes in synaptic integrity. We hypothesize that these ultrastructural changes in neuronal and synaptic morphology will compromise synaptic plasticity and cognitive function. We have also recently found that irradiation leads to a rapid and persistent upregulation of cannabinoid receptors (type 1, CB1) that is associated with cognitive dysfunction. Electrophysiologic measurements have confirmed that irradiation significantly alters CB1 mediated neurotransmission thereby perturbing the inhibitory/excitatory tone of the irradiated brain. The CB1 receptor is a major pre-synaptic modulator of neurotransmitter release, and our data suggest that cytotoxic cancer treatments disrupt cannabinoid signaling in the brain with significant adverse effects on cognition. Importantly, we have now uncovered new data demonstrating that a non-toxic, blood brain barrier permeant antagonist (inverse agonist) of CB1 receptors, namely AM251, can prevent radiation-induced cognitive impairment when administered after irradiation. We will explore whether this novel strategy targeted to the cannabinoid-signaling axis, provides a potential therapeutic intervention for reducing the adverse effects of cytotoxic cancer treatments in the brain. Regional differences in the sensitivity of specific neuronal populations in the hippocampus and medial prefrontal cortex will be investigated after treatment to elucidate further the acute and chronic mechanisms that destabilize synaptic strength, connectivity and functionality in the injured CNS.